Structure–activity and High‐content Imaging Analyses of Novel Tubulysins

Abstract

The synthesis and biological evaluation of three tubulysin analogs provides the first structure-activity relationship in this family of potent cytotoxic myxobacteria metabolites. Most importantly, the labile N,O-acetal at N(14) is not essential for biological activity. Further, structural simplifications are possible without abolishing biological activities. The N-terminal amino acid can be replaced with N-methylsarcosine, and the configuration at the acetoxy-bearing stereocenter at C(11) is important but not critical for almost all aspects of the biological profile. Our data encourage further development of these compounds as potential therapeutic agents in cancer treatment.

Synthesis of a Cyclic Analogue of Tuv N-Methyl Tubulysin

“…5 Although the highly potent tubulysins (tubulysins A-I) have an unusual N,O-acetal on the Tuv-amide, the N,O-acetal is not essential for picomolar cytotoxicity. 6 Indeed, tubulysin D and its Tuv N-methyl analogue 7 (R 1 = Me, R 2 = Ac, R 3 = H) were equally potent. 8 A drop in activity was only observed when the N-substituent was completely removed (R 1 = H).…”

Prätubulysin, eine potente und synthetisch leicht zugängliche Vorstufe von Tubulysin aus Angiococcus disciformis

“…[7] Trotz der vermeintlichen Einfachheit der Tup-Einheit ist die stereoselektive Einführung der a-Methylgruppe nicht trivial. [5,9] Da unsere ersten Versuche -durch Enolat-Alkylierung -nicht erfolgreich waren, wandten wir uns dem pragmatischen Weg der katalytischen Hydrierung zu. Der benötigte a,b-ungesättigte Ester 8 war einfach aus geschütz-tem Phe durch Dibal-Reduktion/Wittig-Olefinierung zugänglich (Schema 3).…”

“…Die katalytische Hydrierung von 8 ergab eine 2:1-Mischung der diastereomeren Tup-Derivate. Leider brachte die Hydrierung der freien Säure (wie von Wipf et al beschrieben [5] ) oder des entsprechenden Allylalkohols keine signifikante Verbesserung. Da Zanda et al eine chromatographische Trennung der entsprechenden Menthylester beschrieben haben, [9] überführten wir 8 in den Menthylester 9.…”

Polymeric Tubulysin-Peptide Nanoparticles with Potent Antitumor Activity

“…Because TubA does not contain any thiol groups, this strategy required derivatization of the molecule. Recently, multiple, fully synthetic tubulysin analogs have successfully been synthesized, enabling the study of the structure-activity relationship of these compounds (1). Based on these results, we hypothesized that the introduction of a marcaptoethyl amide group at the carboxy-terminus of TubA may be possible without causing a significant loss of target inhibition and cytotoxicity.…”

“…Tubulysins have also been found to be active in tumors that exhibit a multidrug resistance phenotype, especially in those with up-regulated surface p-glycoprotein pumps (7). Total synthesis of multiple tubulysin analogs and accompanying structure-activity relationship studies have revealed several analogs with equal or greater activity compared with the natural compounds that are both easier to synthesize and also more stable under physiologic conditions (1,13).…”